Glycogen synthase kinase 3 beta (GSK-3 beta) is constantly active in cells and its activity increases after serum deprivation, indicating that GSK-3 beta might play a major role in cell survival under serum starvation. In this study, we attempted to determine how GSK-3 beta promotes cell survival after serum depletion. Under full culture conditions (10% FBS), GSK-3 beta inhibition with chemical inhibitors or siRNAs failed to induce cell death in human prostate cancer cells. By contrast, under conditions of serum starvation, a profound necrotic cell death was observed as evidenced by cellular morphologic features and biochemical markers. Further analysis revealed that GSK-3 beta-inhibition-induced cell death was in parallel with an extensive autophagic response. Interestingly, blocking the autophagic response switched GSK-3 beta-inhibition-induced necrosis to apoptotic cell death. Finally, GSK-3 beta inhibition resulted in a remarkable elevation of Bif-1 protein levels, and silencing Bif-1 expression abrogated GSK-3 beta-inhibition-induced autophagic response and cell death. Taken together, our study suggests that GSK-3 beta promotes cell survival by modulating Bif-1-dependent autophagic response and cell death.